The objective of this new Conte Center is to study the role of the brain's appetitive neural circuits in the regulation of mood and motivation as they relate to depression and antidepressant action. The program of research contains three major strengths. First, is the multidisciplinary nature of our ongoing and proposed research. Each research area represents an integration of molecular, cellular, pharmacological, and behavioral levels of analysis aimed at obtaining a more complete understanding of the neurobiology of mood. Second, is the integration of our basic science research with the investigation of clinical populations. Third, is the extraordinary degree of integration of the various Projects to examine highly related aspects of the central hypothesis of the Center. While research in depression has focused largely on hippocampus and cerebral cortex, other neural circuits possibly involved have received much less attention. This Center focuses on one of these other circuits, namely, appetitive regions of brain, including nucleus accumbens and hypothalamus, important for motivation, reward, appetite, sleep, psychomotor activity, and circadian rhythms. A focus on these appetitive circuits makes sense given the degree to which abnormalities in these various domains are seen in patients with depression and other mood disorders. Indeed, we have obtained substantial evidence, presented in this application, for the importance of these appetitive circuits in animal models of depression. The Center is organized into a small Coordination Core, two scientific Cores, and five Projects. The Transgenic Core is responsible for providing state-of-the-art molecular tools to Center investigators, while the Behavioral Core is responsible for providing to individual Projects an extremely broad battery of behavioral tests in mice and rats relevant to mood and motivation. Project 1 is focused on the transcription factor CREB as a key regulator of appetitive circuits and its role in mood and motivation. Subsequent Projects evaluate a series of other molecular signals in these neural pathways that are both important regulators of CREB function and important effectors in mediating CREB's behavioral phenotype. Project 2 focuses on BDNF; Project 3 focuses on three hypothalamic peptides, MSH, orexin (hypocretin), and MCH; Project 4 focuses on NPAS2 and other circadian genes; Project 5 focuses on RGS proteins, in particular, RGS9 and RGS16.